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Clinical Trials of Ovarian Cancer Immunotherapy and Future Directions 

Clinical Trials of Ovarian Cancer Immunotherapy and Future Directions
Chapter:
Clinical Trials of Ovarian Cancer Immunotherapy and Future Directions
Author(s):

Justin M. Drerup

, Curtis A. Clark

, and Tyler J. Curiel

DOI:
10.1093/med/9780190248208.003.0013
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date: 15 October 2019

Introduction

Ovarian cancer (OC) is thought to result from uncontrolled growth of epithelial cells surrounding the ovaries, stromal cells, or ova, although specific cells of origin for various histologic types are incompletely understood.1 Epithelial OC is by far the most common OC subtype, and all discussion in this chapter refers to epithelial OC. Nearly 80% of OC patients present with regional or distant OC metastasis, and, although OC responds well to initial chemotherapy and surgical debulking, more than half of patients succumb to chemoresistant relapse within five years of diagnosis. Immunotherapy could be a viable treatment modality2,3,4,5,6,7,8,9 as there are a number of immunogenic OC-associated antigens that provoke detectable and specific T-cell responses.10,11,12,13,14,15,16,17,18,19 Intratumoral CD8+ T-cell density positively correlates with OC patient survival, a seminal finding that supports the role of anti-tumor immunity in slowing OC progression.20 However, in spite of abundant evidence that immune therapy could be effective for OC, clinical trials have been, at best, humbling with only modest successes. The earliest attempts at immunotherapy for OC unsuccessfully employed intraperitoneal instillations of anti-human milk fat globulin-1 antibodies in 1987,21 which was among the very first uses of antibodies as cancer immunotherapy. A number of similar attempts followed, most notably with failure of the anti-CA-125 antibody oregovomab. Although many anecdotal reports of newer immunotherapy approaches indicate positive patient outcomes and high-profile successes in other solid tumors (e.g., melanoma and lung cancer), there is currently no Food and Drug Administration (FDA)–approved immune therapy for OC. Nonetheless, new data suggests that effective, tolerable OC immunotherapy could be developed. A more complete understanding of OC immunopathogenesis, OC rejection antigens, the role of immune-suppressive regulatory T cells and immature myeloid cells, and dysfunctional immune co-signaling help identify new and possibly more effective approaches to activate anti-OC immunity. As with chemotherapy, combination immunotherapies appear more promising than single agents. An important area for future trials is to determine optimal combinations of immunotherapy, cytotoxics, targeted inhibitors, radiation therapy, or surgery with the ultimate goal of developing comprehensive, multimodal, and potentially curative OC treatment regimens. Here we describe the current state of OC immunotherapy clinical trials and comment on future directions.

Chemotherapy as Immunotherapy

Several cytotoxic agents act as immune modulators and can reduce immunosuppressive cells or increase tumor immunogenicity. Fludarabine22 or cyclophosphamide23 can deplete immunopathogenic regulatory T cells. 5-fluorouracil can deplete cancer-promoting myeloid-derived suppressor cells in preclinical models.24 Anthracyclines can promote immune surveillance by causing release of tumor antigens by tumor cell lysis or release of danger signals, such as high-mobility group box 1.25 Thus, chemotherapy is a rational adjunct to immune therapy to increase tumor immunogenicity or impair immune suppressive cells.

Monoclonal Antibodies

Anti-Milk Fat Globulin-1

Nearly three decades ago, intraperitoneal radiolabeled anti-milk fat globulin antibodies were tested as OC immunotherapy,21 where dose of irradiation correlated with occasional treatment responses. Further trials continued to establish the safety of intraperitoneal antibody instillation, demonstrating that this could be a viable route to concentrate drug at the site of OC tumors.26 A Phase II trial of90yttrium-labeled anti-human milk fat globulin-1 in 25 patients failed to produce meaningful objective responses, and dose escalation produced myelosuppression that limited this approach.27

However,90yttrium-labeled anti-human milk fat globulin-1 was later tested in 52 patients in combination with surgical debulking and chemotherapy.28 Twenty-one of 52 patients had no evidence of disease at therapy cessation, with a median survival of 35 months that compared favorably to historical controls. A seven-year follow-up corroborated potential efficacy.29 Further trials indicate that a major limitation was the inability of anti-milk fat globulin 1 to control distant relapses that reduced any advantages conferred by reduction of intraperitoneal tumor burden.30

Farletuzumab

Farletuzumab is a humanized anti-folate receptor-α‎ antibody (folate receptor is elevated in many OCs) that does not inhibit folate transport but stimulates antibody-mediated cytotoxicity against folate receptor-expressing cells. Phase I and II trials demonstrated safety and activity in chemoresistant OC patients.31,32 Fifty-four OC patients received weekly farletuzumab alone or combined with carboplatin with paclitaxel or docetaxel.31 Farletuzumab monotherapy was well tolerated and did not potentiate side effects typically seen with chemotherapeutics. Of 47 patients on farletuzumab plus chemotherapy, 38 (80.9%) normalized CA-125. Complete or partial response rates were 75% with farletuzumab plus cytotoxics. Thus, farletuzumab alone might be poorly effective, but combination with carboplatin plus a taxane was thought to merit additional consideration in the context of chemoresistant relapsed patients. Very disappointingly, chemotherapy followed by farletuzumab failed to improve progression-free or overall survival at two doses in a recently published Phase III trial of 1,100 platinum-resistant OC patients,33 although survival trended to be improved in patients with the lowest tumor burden (as indicated by pre-farletuzumab CA-125 levels).

Catumaxomab

Catumaxomab targets epithelial cell adhesion molecule (EpCAM)–expressing tumor cells thought to mediate ascites accumulation. It is approved in Europe but not the United States to treat malignant ascites. Adverse effects include fever, nausea, vomiting, and abdominal pain. A Phase IIIb study demonstrated that 25 mg prednisolone mitigated adverse events.34 Because catumaxomab is a rat-mouse hybrid antibody, xenoantibodies could modulate its efficacy. OC patients treated with catumaxomab exhibited increased latency to subsequent paracentesis as expected but surprisingly also experienced significantly increased median overall survival.35

Immune Checkpoint Inhibitors

Compared to any other immunotherapy, immune checkpoint blockade antibodies have accumulated the most evidence of increased patient overall survival and long-term responses in solid tumors. Highly anticipated clinical trial successes culminated in the FDA approval of ipilimumab (anti-CTLA-4), pembrolizumab (anti-PD-1), and nivolumab (anti-PD-1) for melanoma and non-small cell lung cancer (and, very recently, avelumab [anti-PD-L1] for advanced bladder cancer). These checkpoint inhibitors block negative regulatory signals from PD-L1+ cancer cells or antigen-presenting cells that cause T-cell exhaustion,36 although very recent preclinical studies demonstrate that cancer-cell intrinsic PD-1/PD-L1 signaling is directly advantageous for tumor growth, independent of immunity.37,38 Thus, direct effects on tumor are potential additional mechanisms of action for PD-1 or PD-L1 blocking antibodies. Due to these unprecedented trial successes, antibodies targeting several other checkpoint proteins are now in various stages of preclinical and clinical development, including against Tim3, LAG-3, or TIGIT. Tremelimumab, like ipilimumab, is a fully human anti-CTLA-4 checkpoint antibody. Ipilimumab became the first approved checkpoint inhibitor following Phase III trials demonstrating efficacy against metastatic or unresectable melanoma.39 Anecdotal ipilimumab efficacy against OC prompted an ongoing Phase II trial of ipilimumab in treatment-resistant OC (NCT01611558). Ipilimumab has significant immune-related side effects that include off-target inflammation that is occasionally life-threatening but generally resolves after administration of corticosteroids or immune-suppressive monoclonal antibodies (e.g., infliximab). Tremelimumab (in Phase III trials for melanoma) could have similar efficacy with reduced toxicities. Avelumab, an anti-PD-L1 antibody, was recently FDA approved for bladder cancer and multiple studies continue to provide a rationale for PD-L1 as a therapeutic target in many cancer types.40 BMS-936559 is a fully human monoclonal antibody that prevents PD-L1 from ligating its known cognate receptors, PD-1 and CD80. It demonstrated safety in a Phase I trial that included 17 OC patients.40 Adverse events occurred in 91% of 207 total patients. However, just 6% halted therapy due to side effects. Common adverse events included fatigue, infusion reactions, diarrhea, arthralgia, pruritis, rash, nausea, and headache. Immune-related adverse events (rash, hypothyroidism, hepatitis, sarcoidosis, diabetes mellitus, endophthalmitis, myasthenia gravis) were observed in 81 patients (39%). Objective responses among OC patients were generally modest and only observed at the highest dose of 10 mg/kg: one patient (6%) with a partial response and three (18%) with stable disease (>24 weeks). Anti-PD-L1 is currently being tested in multiple clinical trials as monotherapy or in combination with other immune-modulating antibodies. A Phase I/II clinical trial will test anti-PD-L1 alone in patients with advanced, treatment-refractory solid tumors, including OC (NCT01693562). Several other trials examine the combination of anti-PD-L1 with anti-CTLA-4, anti-PD-1, or anti-OX-40 (an agonistic antibody that stimulates T cell activation) (NCT02205333, NCT02118337, NCT02261220). Pembrolizumab (anti-PD-1 antibody) is currently under investigation in a Phase 1b trial for patients with biomarker-positive solid tumors, including OC (NCT02054806).

In OC, there is some evidence that clear cell histology is more immunotherapy sensitive versus the more common high-grade serous histology. For example, one of two patients with clear cell OC experienced a complete clinical response in a trial of nivolumab for platinum-refractory disease.41 In a Phase 1b trial of the anti-PD-L1 antibody avelumab in OC, two of two patients with clear cell histology had partial clinical responses.42

CD137 (4-1BB) is a stimulatory immune checkpoint protein that promotes T-cell responsiveness. In preclinical OC models, anti-CD137 plus anti-Tim343 or anti-PD-144 improved immune and clinical responses. Anti-CD137 has moved into Phase I human clinical trials that include patients with OC.45 Urelumab targets CD137 through agonistic stimulation and has also entered early clinical trials against solid tumors, including OC as a single agent (NCT01471210) or combined with anti-PD-1 (NCT02253992). Antibodies blocking LAG-3, another T-cell checkpoint protein, recently entered Phase I/II clinical trials for patients with solid tumors, including OC (NCT01968109).

Oregovomab

The OC tumor-associated antigen CA-125 is used as a biomarker for treatment responses. Oregovomab, a murine IgG1 monoclonal antibody that complexes with CA-125 in vivo, can prime dendritic cells (DCs),46 activating anti-tumor T cells.47 In a Phase III study of 373 OC patients48, oregovomab used as maintenance after first-line therapy was well tolerated, although without significant clinical efficacy, causing initial abandonment. However, as previous reports indicated immune-boosting effects,46,47,48 renewed interest in oregovomab prompted current use in combination with first-line chemotherapy (carboplatin plus paclitaxel) in a Phase II randomized trial of advanced OC (NCT01616303). In addition to clinical end points, this study will also assess immune-modulating effects of anti-CA-125.

Abagovomab

The anti-idiotypic CA-125 murine monoclonal antibody, abagovomab,49 is proposed to function by inducing anti-CA-125 antibodies. The most common adverse events were minor injection site pain, myalgia, and fever in a Phase I trial of 42 OC patients randomized to intramuscular versus subcutaneous abagovomab vaccination (2.0 or 0.2 mg four times every two weeks, plus two additional monthly vaccinations). In addition to anti-CA-125 antibodies, human anti-mouse antibodies (irrespective of dose or administration route) were detected in all patients.50 Abagovomab as maintenance therapy (2 mg or placebo initially administered every two weeks for six weeks, followed by maintenance vaccinations every four weeks until recurrence), induced a robust anti-CA-125 response without increase in recurrence-free or overall survival in a recent Phase III trial (the MIMOSA study) of 888 patients with stage III or IV OC51 in complete clinical remission after front-line surgery plus platinum/taxane chemotherapy. Patients were treated for 450 days on average, and minor adverse events were similar to those in the Phase I trial. Subsequent studies confirmed the inability to extend overall survival in OC52 or to expand CA-125-specific CD8+ T cells. Nonetheless, as elevated CA-125-specific CD8+ T cells can predict increased survival,52 stimulation of CA-125-specific cytotoxic lymphocyte responses remains a viable OC treatment strategy.

Volociximab

Targeting the integrin subunit AAB1, volociximab is a chimeric IgG4 monoclonal antibody with anti-neoangiogenic properties by blocking interaction of α‎5β‎1integrin with fibronectin.53 In a Phase II trial of 16 patients with platinum-resistant OC or primary peritoneal cancer,54 intravenous volociximab (15 mg/kg weekly until disease progression or treatment intolerance) elicited stable disease in one patient at eight weeks, but all others progressed. Headache and fatigue were common adverse events in 75% of patients, while posterior leukoencephalopathy syndrome, pulmonary embolism, and hyponatremia were possible study-related, serious but reversible adverse events in three patients. Results from this trial have incited additional investigations.

Amatuximab

Mesothelin is a tumor differentiation antigen overexpressed in certain cancers including OC55 and is a thus a candidate OC treatment target. In a Phase I trial of 24 patients with mesothelin-expressing tumors including OC, the chimeric anti-mesothelin monoclonal antibody MORAb-009 (amatuximab) effected stable disease in 11 patients,56 prompting an ongoing Phase II trial in mesothelioma patients.

Tocilizumab/Siltuximab

Interleukin (IL)-6 in immunopathologic in diverse cancers57 and plays varied immunopathogenic roles in OC.58,59 Tocilizumab is a humanized anti-IL-6 receptor antibody tested for tumor cachexia60 and mitigation of cytokine release symptoms in adoptive T-cell therapy.61 A Phase I trial tested tocilizumab plus chemotherapy in 23 OC patients,62 finding it to be safe and tolerable. Objective responses were observed in 11 of 21 evaluable patients (6 stable disease, 3 progressive disease). Likewise, the anti-IL-6 antibody siltuximab is being explored as therapy for numerous carcinomas, hematologic malignancies, and cachexia.63 Siltuximab was evaluated in a Phase I/II trial of patients with solid tumors (including 29 OC patients)64 and was well tolerated but without clinical efficacy. Various trials are currently underway, including use in cancer, evaluating anti-IL-6 and anti-IL-6 receptor antibodies.

Other Monoclonal Antibody Clinical Trials in Progress

Immunotherapy is being tested in a wide-range and number of clinical trials involving solid tumors. In one study involving platinum-resistant OC patients, the cytotoxic agent MMAE is being tested as a drug/antibody conjugate that targets the type II sodium-phosphate cotransporter, which is overexpressed on many ovarian and lung cancers (NCT01991210). In Phase I/II trials in patients with platinum-resistant OC, demcizumab and OM-P52M51 antibodies are being investigated in their ability to inhibit Notch-dependent cancer cell-intrinsic growth pathways by targeting delta-like ligand-4 or Notch1, respectively (NCT01952249 and NCT01778439). In a multicenter Phase I/II trial, monoclonal antibodies specific for Trop-2, which is overexpressed in many epithelial carcinomas and preclinical studies implicate its role in cancer cell invasion, survival, and stemness,65 are being tested in patients with epithelial cancers, including OC (NCT01631552). Antibody-based therapy for cancer has been previously reviewed in detail.66

Additional Approaches

Targeting detrimental regulatory T cells in human malignancies, including OC, remains a practical therapeutic strategy. Our recent report of a Phase I clinical trial using denileukin diftitox fusion toxin demonstrated the potential benefit of reducing regulatory T cells and eliciting enhanced anti-tumor immunity in human cancer, in which a significant partial clinical response in one patient with metastatic OC was observed. In a subsequent Phase II trial of 28 OC patients, administration of denileukin diftitox (12 μ‎g/kg every three to four weeks) was well tolerated with no more than grade 2 toxicities (most commonly fatigue, fever, myalgias) but failed clinically, despite reducing blood regulatory T (Treg) cells.67 We recently reported preclinical findings that immune checkpoint blockade greatly enhances denileukin diftitox clinical efficacy, including in OC,68 which has encouraged ongoing studies of combination strategies. Our preclinical studies have also suggested that anti-CD73 could improve clinical efficacy of adoptive T-cell transfer in OC69 and demonstrated that age70 and sex71 alter immunotherapy outcomes, significant factors generally not taken into account in immunotherapy trial design.

Cytokines

Interferon-α‎

Type I interferons (primarily interferons α‎, β‎, and ω‎) were originally identified as anti-viral proteins72 but have subsequently been found to block malignant cell proliferation. Studies of type I interferons in human cancer have primary focused on interferon-α‎ and using relatively high doses that directly inhibit tumor cell replication, despite significant toxicities that limit clinical applications.73 Initially evaluated in the early 1980s as one of the first OC immunotherapy approaches, intraperitoneal interferon-α‎ exhibited only modest clinical efficacy.74,75 A Phase II study of 14 OC patients demonstrated that interferon-α‎ could be administered intraperitoneally in combination with cis-platinum as salvage therapy when optimal surgical debulking was not obtainable. This approach was tolerable with indications of clinical efficacy,76 but intraperitoneal interferon-α‎ also failed to manage malignant OC ascites.77

Interferon-α‎ improved paclitaxel clinical efficacy in a preclinical OC mouse model.78 In vitro, interferon-α‎ upregulated OC cell human leukocyte antigen class I,79 indicating the potential for enhanced anti-tumor immune recognition, whereas potential OC antigen targets such as HMFG1 and HMFG2 were downregulated, altogether emphasizing that multiple factors must be considered when designing combination therapies.

In our subsequent and ongoing studies, interferon-α‎ at low, immune-modulating doses improved the immune and clinical efficacy of denileukin diftitox used to deplete regulatory T cells in a mouse OC model and in two of two OC patients, with manageable toxicities.80 As an additional possible mechanism of action, interferon-α‎ reduces proliferation of human OC stem cells81 that play major roles in initiation, perpetuation, and development of cancer treatment resistance. Expression of interferon-β‎ by engineered adenoviruses was used as gene therapy in an early-phase clinical trial that included two OC patients,82 in which one patient demonstrated stable disease two months after treatment ended. However, both patients died within five months of treatment initiation. Despite generation of anti-tumor antibodies, development of neutralizing anti-adenovirus antibodies, a well-known limitation of repeated adenovirus administrations, reduced interferon-β‎ levels after the second adenovirus infusion.

Interferon-γ‎

By 1992, interferon-γ‎ was established to treat OC,83 and by 1996, intraperitoneal administration of interferon-γ‎ elicited some promising preliminary results.84 Interferon-γ‎ in combination with front-line chemotherapy was confirmed to improve OC survival.85 In combination with interleukin-2, interferon-γ‎ was studied with infusion of tumor-infiltrating lymphocytes in OC. Either alone or combined with interleukin-2, interferon-γ‎ upregulated tumor cell human leukocyte antigen class I and class II expression,86 potentially improving tumor immunogenicity. Two of 22 OC patients receiving cytokine treatments also received tumor-infiltrating lymphocyte adoptive transfer after ex vivo expansion, and one of these two had disease stabilization lasting >6 months. In combination with IL-2 therapy, interferon-γ‎ activated CD8+ T cells but also stimulated expression of possibly immunosuppressive IL-10 and TGF-β‎.

Interferon-γ‎ to boost antibody-dependent cellular cytotoxicity was investigated in a Phase I clinical trial of 25 possibly chemotherapy-sensitive OC patients with recurrent measurable disease. Administration of GM-CSF (starting at 400 μ‎g/day subcutaneously) for seven days plus interferon-γ‎ (100 μ‎g subcutaneously, on days 5 and 7), before and after intravenous carboplatin (AUC 5) increased activation of blood monocytes but without definitive alteration of antibody-dependent cellular cytotoxicity.87

Interferon-γ‎ significantly improved survival in mouse OC xenograft models, while administration of the matrix metalloprotease inhibitor batimastat but not carboplatin enhanced survival with interferon-γ‎.88 In vitro, interferon-γ‎ downregulated Her2 and inhibited cell proliferation in multiple human OC lines89 and augmented OC cell susceptibility to CA-125 (tumor)-specific CD8+ T cell-mediated cytotoxicity.90 Thus, interferons deserve additional consideration in immunotherapy trials in OC.

Interleukin-2

IL-2, first identified as an in vitro T-cell growth factor, is among the first effective cancer immunotherapies.91 It exerts modest anti-cancer activity in melanoma and renal cell carcinoma, among other cancers.92 During its initial human trials, a small fraction of patients (with aggressive cancers that failed all prior therapies) exhibited long-term cancer-free survival (putative cures), an immunotherapy first. A major limitation of IL-2 therapy is toxicity due to vascular leak syndrome caused by stimulation of IL-2 receptor on endothelial cells, as well as IL-2-mediated expansion of immune suppressive regulatory T cells in OC.93 Because IL-2 was later found to be a Treg growth and differentiation factor, combining IL-2 with specific Treg depletion could be useful clinically. Low-dose IL-2 plus retinoic acid was tested in an OC cohort.94 Five-year progression-free survival and overall survival rates were 29% and 38%, respectively, in 65 patients. Notable observations included a lowering of vascular endothelial growth factor and augmentation of lymphocyte and natural killer (NK) cell numbers. In a Phase II trial of 31 chemoresistant OC patients,95 intraperitoneal IL-2 elicited minor clinical efficacy but with few major adverse events, indicating this route of administration could be superior to intravenous IL-2. In 24 patients so assessed, there were four complete and two partial clinical responses with overall survival positively correlating with cytokine-expressing cytotoxic T-cell numbers. A combination of IL-2 plus erythropoietin was tested in peripheral blood stem cell transplants for breast cancer and OC. Myeloid cell recovery was improved, but there were no significant immune benefits.96

IL-2/anti-IL-2 cytokine-antibody complexes can harness the ability of IL-2 to stimulate effector T and NK cells but avoid Treg expansion and vascular leak syndrome. In preclinical studies, when IL-2 is complexed with anti-IL-2 antibodies that occlude the CD25-binding moiety of IL-2, IL-2 will stimulate only low-affinity IL-2 receptor, and thus there is predominantly expansion of effector, but not regulatory, immune cells, which has reduced tumor burden in several mouse cancer models.97 Development of clinical-grade CD122-specific anti-IL-2/IL-2 complexes will be an important area of future development for cancer immunotherapy with IL-2. We recently reported that a CD122-directed IL-2 complex (targeting the intermediate-affinity IL-2 receptor) improved anti-cancer immunity, reduced tumor growth, and improved survival in an aggressive model of mouse OC,98 providing rationale for translation of IL-2 complexes into OC trials.

Tumor Necrosis Factor α‎

Tumor necrosis factor alpha (TNF-α‎) induces cancer cell apoptosis and boosts anticancer immunity. A fusion protein of TNF-α‎ and the tripeptide asparagine-glycine-arginine (NGR-hTNF) selectively binds CD13, a molecule overexpressed on tumor blood vessels. NGR-hTNF has higher potency versus native TNF-α‎ and reduces toxicities. Thirty-seven patients with platinum-resistant OC received a median four cycles of NGR-hTNF.99 Partial clinical responses were achieved in 8 (23%), and stable disease was achieved in 15 (43%). Common side effects included weakness, leukopenia, anemia, nausea, neutropenia (including one instance of febrile neutropenia), chills, constipation, and vomiting. Nonetheless, <10% of these adverse events were attributed to NGR-hTNF. In contrast, preclinical data now suggest that TNF-α‎ promotes OC cell-intrinsic growth in humans and mouse OC cell lines.100,101 Thus, TNF-α‎ inhibitors (of which some are already FDA approved) warrant testing as OC therapy.

IL-18

In mouse models, recombinant IL-18 (SB-485232) improves antitumor immunity when combined with PEGylated liposomal doxorubicin. SB-485232 was used with PEGylated liposomal doxorubicin in a Phase I study of patients with recurrent OC. Sixteen patients were treated with four PEGylated liposomal doxorubicin cycles (40 mg/m2) every 28 days, in combination with dose-escalated SB-485232 on cycle days 2 and 9. Eighty-two percent of patients were platinum-resistant/refractory and heavily pretreated. SB-485232 was well tolerated. PEGylated liposomal doxorubicin did not affect SB-485232 biologic activity, and SB-485232 did not alter toxicities of doxorubicin. Thirty-eight percent of patients had stable disease, but improved clinical responses were modest.102

A summary of recent selected clinical trials using antibodies, immunotoxins, or cytokines is presented in Table 13.1.

Table 13.1 Selected Recent Clinical Trials in OC that Use Antibodies/Immunotoxins or Cytokines

Clinical Trial Approach

Clinical Trial

No. OC Patients

Objective Responses

Reference or Trial ID

Antibodies and Immunotoxins

Phase II trial of farletuzumab (anti-folate receptor) ± carboplatin or a taxane, 2013

54

44–CR/PR, 10–PD or N/A

31

Phase I trial of farletuzumab, 2010

25

9–SD, 15–PD, 1–N/A

32

Phase II trial of ipilimumab (anti-CTLA-4) ongoing

N/A

N/A

NCT01611558

Phase I trial of BMS-936559 (anti-PD-L1), 2012

17

1–PR, 3–SD, 13–PD

42

Phase II trial of oregovomab ± paclitaxel or paclitaxel/carboplatin, ongoing

N/A

N/A

NCT01616303

Phase III trial of abagovomab (anti-CA-125 idiotype), 2013

888

No change in recurrence free or overall survival

51

Phase II trial of volociximab (anti-α‎5β‎1 integrin), 2011

16

1–SD, 15–PD

54

Phase I trial of amatuximab (MORAb-009, anti-mesothelin), 2010

4

0–CR/PR

56

Phase 0/I trial of denileukin diftitox (IL-2/diphtheria fusion toxin)

4

1–PR

67

Phase II trial of denileukin diftitox, 2014

28

26–PD

2–SD

67

Phase III trial of farletuzumab in platinum-resistant OC patients

1100

Failed to improve overall and PFS

33

Phase I trial of siltuximab (anti-IL-6 receptor) in solid tumors, including OC

29

No objective responses occurred

64

Phase I/II trial of anti-PD-L1 in solid tumors including OC, ongoing

N/A

N/A

NCT01693562

Combination immunotherapy with anti-PD-L1, anti-CTLA-4, anti-PD-1, and anti-OX40 for solid tumors including OC, ongoing

N/A

N/A

NCT02205333, NCT02118337, NCT02261220

Phase 1b trial of anti-PD-1 (pembrolizumab) for solid tumors including OC, ongoing

N/A

N/A

NCT02054806

Phase I of urelumab alone or in combination with anti-PD-1 for solid tumors including OC, ongoing

N/A

N/A

NCT01471210

NCT02253992

Phase I of anti-LAG-3 in solid tumors including OC, ongoing

N/A

N/A

NCT01968109

Cytokines

Phase II trial of NGR-hTNF+ doxorubicin, 2012

35

8–PR, 15–SD, 7–PD

99

Phase I trial of IL-18 + pegylated liposomal doxorubicin, 2013

15

1–PR, 6–SD,

8–PD

102

Phase II trial of denileukin diftitox plus subcutaneous pegylated interferon-α‎

3

2–SD

1–PD

80

Phase II trial of intraperitoneal IL-2 instillation in platinum resistant OC patients

24

4–CR

2–PR

95

NOTE: OC = ovarian cancer; PD = progressive disease; IR = initial response; CR = complete response; CCR = continued clinical response; PR = partial response; SD = stable disease; NED = no evidence of disease; NR = no response; N/A = not available; PFS = progression-free survival; OS = overall survival.

Other Treatments

Peptide Vaccines

Although the mutational load in OC is low compared to many epithelial carcinomas, a number of tumor-associated antigens have been identified. Thus, there is potential to elicit beneficial anti-tumor immunity. Identified OC tumor-associated antigens to date include HER2/neu, MUC1,10 membrane folate receptor,12 NY-ESO-1,11 folate binding protein (gp38),13 mesothelin,15,16 TAG-72,14 milk fat globulin-1,21 sialyl-Tn,17,18 and OA3.19

A significant limitation of peptide vaccines is that they are recognized in the context of specific major histocompatibility complex molecules and thus will generally not be widely applicable. Using peptide library vaccines or rapid synthesis of patient-specific peptides are currently being investigated for cancers generally and could help overcome this limitation.103

NY-ESO-1

NY-ESO-1 is a cancer/testis antigen found in some OCs. It was delivered in vaccinia or fowlpox vectors and given to 22 patients with advanced OC in clinical remission.104 One intradermal dose of NY-ESO-1-vaccinia vector followed by monthly subcutaneous NY-ESO-1-fowlpox vector increased NY-ESO-1 specific antibodies. Median duration of progression-free survival and median overall survival were 21 months and 4 years, respectively, with no major adverse events.

In a Phase I trial with 12 patients with relapsed OC, the epigenetic modifier decitabine and liposomal doxorubicin were combined with an NY-ESO-1 vaccine. Treatment was safe and with manageable adverse events. Vaccination augmented NY-ESO-1-specific antibodies as well as antibodies to additional distinct OC tumor antigens. Stable disease or partial clinical response was observed in 6 of 10 patients,105 prompting further studies.

p53

p53 overexpression is common in selected OC types. p53 peptide vaccination in addition to IL-2, GM-CSF and montanide adjuvant was tested in patients with stage II or IV or recurrent OC with p53 overexpression. Vaccination augmented anti-p53 immunity (p53-specific T cells and interferon-γ‎) in 9 of 13 patients.106 Vaccination using subcutaneous versus intravenous p53-pulsed DC infusion with IL-2 to boost T-cell function was assessed. Comparable immunity was demonstrated by either vaccine route.106 Thus, subcutaneous vaccination could be a logistically easier route for further trials. Clinical data were not reported in this trial. It was also noted that IL-2 augmented blood Treg numbers. As Tregs can defeat OC-specific immunity9, more work on this adjuvant approach is needed. In a separate Phase II trial, a long synthetic p53 peptide was assessed in recurrent OC. This peptide induced antigen-specific T cells but without clear clinical benefit, even when combined with chemotherapy.107

Naturally Occurring Cancer Peptides

DPX-0907 (DepoVax) is a peptide adjuvant that is oil based. In a Phase I trial of patients with advanced-stage breast cancer, prostate cancer, or OC, naturally occurring HLA A2-expressed cancer peptides (from cell lines) in this vaccine were well tolerated and immunogenic when DPX-0907 as adjuvant was used.108 The most common adverse effect was injection-site reactions. Polyfunctional T cells, including in OC patients, were generated, leading to more studies in progress (NCT01416038).

Carcinoembryonic Antigen Glypican-3

A GPC3-derived peptide vaccine in incomplete Freund’s adjuvant was tested in a Phase II OC trial. Patients were vaccinated biweekly six times and then every six weeks until they progressed clinically. Two partial clinical responses were observed in chemorefractory OC patients.109

Carcinoembryonic Antigen and MUC1

In a Phase I clinical trial, 25 patients were primed using vaccinia virus expressing the costimulatory molecules CD80, intercellular adhesion molecule 1, and lymphocyte function-associated antigen 3, and the cancer antigens CEA and MUC-1 (PANVAC-V). Immunity was boosted with fowlpox expressing the same molecules (PANVAC-F). Treatments were well tolerated except for some significant local vaccine reactions. CEA-specific and/or MUC-1-specific immunity was elicited in 9 of 16 patients. One patient with clear cell OC had a clinical response lasting 18 months.110

In a follow-up trial, 26 patients received monthly PANVAC vaccinations. The major toxicity again was injection-site reactions. The trial included 14 OC patients. Their median time to progression was two months (range 1–6), and their median overall survival was 15 months, with one complete clinical response. An OC patient who was also treated in the original Phase I trial had a durable response lasting 38 months. The best clinical responses generally occurred in patients with limited tumor burden and fewer lines of prior chemotherapy.111

5T4 Antigen

Preclinical mouse models showed that viral delivery of tumor antigen caused regression of 5T4-expressing tumors in a CD4+ T-cell dependent manner.112 TroVax is the tumor-associated antigen 5T4 delivered in a modified vaccinia virus Ankara vector113 previously tested in prostate cancer,114 renal cell cancer,115 and melanoma116 with only modest results. It is now in a Phase II trial for asymptomatic relapsed OC patients, with disease progression as the primary outcome (NCT01556841). A similar trial is underway in the United Kingdom.

Peptide Vaccine Trials in Progress

There are several antigens that elicit measurable, specific T-cell responses that could mediate immune rejection of OC. FANG is a patient-autologous tumor cell vaccine that is modified to secrete GM-CSF (promoting DC uptake and migration) and shRNA-knockdown of furin (which prevents furin activation of immune-suppressive TGF-β‎). Early Phase I studies demonstrated safety and increases in surrogates of tumor-specific T-cell activation with FANG vaccine. A Phase II trial still underway is testing FANG in combination with bevacizumab (anti-VEGF antibody) in patients with stage III or IV OC (NCT01551745). CDX-1401 is an antibody/vaccine conjugate that targets NY-ESO-1 to DCs by covalent attachment to an anti-DEC-205 (DC marker) antibody. Indolamine-2,3-dioxygenase 1 (IDO1) promotes the formation of tryptophan metabolites that inhibit anticancer immunity. A small molecule IDO1 inhibitor is currently in a Phase II trial for patients with advanced OC (NCT02042430) after a successful Phase I pilot that demonstrated safety and tolerability. A Phase I/II trial is testing CDX-1401 plus a toll-like receptor 3 agonist and an IDO1 inhibitor in patients with OC in remission (NCT02166905). Vaccines against E39 and J65, both folate binding proteins overexpressed in OC, are being tested in a Phase Ib trial in OC patients in remission (NCT02019524). A vaccine developed against Her2 is being tested in a Phase I trial with solid tumors, including OC (NCT01376505).

Adoptive Cell Transfers

DCs

DC effects in cancer therapy have been extensively reviewed.117 Tumor antigen-pulsed DC adoptive transfer improves anti-tumor immunity through anti-tumor T-cell activation. Eleven advanced-stage OC patients in a Phase I/II trial were treated with DC pulsed with Her2/neu, telomerase, and pan T helper cell stimulating (PADRE) peptides either with or without low-dose cyclophosphamide to deplete Tregs.118 Infusions were generally well tolerated. The most common adverse events were low-grade hypersensitivity reactions. Elicited anti-tumor immunity was only modest. However, only 1 of 11 patients died within three years of vaccination. In the other 10 patients, 3 developed chemotherapy-responsive recurrences and the other 7 remained disease-free. Another trial tested autologous whole tumor lysate-pulsed DC plus bevacizumab, cyclophosphamide, and autologous tumor lysate-primed T cells in recurrent OC patients.119 Transfusions were well tolerated. Two of six patients had partial clinical responses, and two others had stable disease. Blood Tregs were reduced and tumor-specific T cells were increased in the four patients with experienced clinical benefit. Long-term follow-up results from this trial are expected shortly.

A Phase II trial of 10 patients with minimal residual OC were given subcutaneous autologous tumor lysate-pulsed DC plus the adjuvant, keyhole limpet hemocyanin and low-dose IL-2.120 Three of 10 patients had complete clinical remissions for 38 to 83 months. A third patient had a complete remission but then relapsed after 50 months. Distinct measures of anti-tumor immunity increased. In patients experiencing clinical benefit, immune outcomes were improved including NK cell activity, TH1-stimulating interferon-γ‎+ T cells, and IL-12, and immunosuppressive TGF-β‎ was reduced. A Phase I trial of an autologous NY-ESO-1-pulsed DC vaccine in combination with the immune-modulator sirolimus (rapamycin) (NCT01522820) is underway for epithelial cancers including OC.

DC/Tumor Cell Fusions

Reinfusion of DC fused to OC cells could present a wider array of tumor antigens versus tumor alone. The concept of DC/tumor cell fusion has been tested in various preclinical models121,122 but not in human OC trials to date to our knowledge.

T Cells

Adoptive transfer of tumor-reactive T cells is a promising approach for future clinical trials, as advances in gene editing technology now allow for reprogramming T-cell specificity toward tumor-associated antigens. Recent technologies have been reviewed.123,124 Seven patients with recurrent local OC in a Phase I trial received repeated cycles of intraperitoneal infusions of autologous MUC1 peptide-stimulated cytotoxic T cells.125 Infusions were well tolerated, multiple versus single infusions were equally effective, and clinical benefit was observed only in one patient, but she remained disease-free >12 years. Another trial from the same group gave intraperitoneal MUC-1 peptide-stimulated PBMCs to seven OC patients with recurrent local disease. Adoptively transferred cells were largely CD4+CD25+ and expressed interferon-γ‎ and IL-10.126 Patients with longer survival had durable levels of IL-10 and interferon-γ‎ producing T cells in peripheral blood, suggesting that cytokines produced by adoptively transferred T cells contributed to long-term survival, although larger numbers and more studies are required to draw conclusions.

TILs

TILs are likely to be enriched in tumor-specific T cells and lend themselves well to ex vivo expansion for autologous reinfusion in patients with pre-existing tumor inflammation. However, there are few published trials testing TIL as therapy in OC. One group tested autologous TILs in combination with chemotherapy. OC patients receiving TIL plus chemotherapy had superior three-year survival rates compared to chemotherapy alone. Therapies utilizing transduced T cells conferring greater tumor specificity have gained in popularity after the underwhelming clinical responses observed with unmodified TIL in numerous cancer types.

Recombinant T Cell Receptors or Chimeric Antigen Receptor Transduced T Cells

Recombinant T cell receptors (TCRs) give T cells MHC-dependent specificity. Chimeric antigen receptor (CAR) T cells are engineered to express surface tumor-antigen specific antibody components. These surface fragments are fused to intracellular activation proteins (e.g., CD3ζ‎, OX40, 4-1BB) and recognize antigens independent of their cognate MHC-peptide complex through the antibody recognition site. A preclinical study found that NKG2D-specific CAR T cells protected against different OC tumors even though only 7% expressed NKG2D.127 CAR T cell efficacy in solid tumors is limited compared to impressive efficacy in leukemia/lymphoma patients due to inefficient tumor homing. Advances in understanding which T cell-attracting chemokines are enriched in OC could improve the efficacy of adoptive T-cell therapy in OC.128 Ex vivo stimulation of CD3/CD28 could upregulate chemokine receptors that promote migration of tumor-specific T cells to the OC tumor mass.128

CAR T cells with folate receptor-α‎ specificity and downstream CD3ζ‎ plus CD137 co-stimulating domains protected from established OC in a mouse model. A Phase I trial of OC patients with recurrent disease using folate receptor-α‎–specific CAR (CD3ζ‎-CD137) T cells is planned.129 We recently reported that follicle stimulating hormone receptor is a useful target for CAR T cell treatment of OC in a preclinical model.130

An ongoing Phase II trial uses lentivirus to transduce autologous T cells with an NY-ESO-1 specific TCR. NY-ESO-1 specific T cells will be reinfused into patients with solid tumors, including OC, after cyclophosphamide preconditioning and adjunct therapy with NY-ESO-1-pulsed DCs and IL-2 (NCT01697527). CAR T cells specific for the VEGF receptor 1 are being tested in a Phase I/II trial for patients with metastatic cancer, including OC (NCT01218867). A Phase I/II trial is now testing autologous NY-ESO-1-specific TCR-transgenic T cells in patients with treatment-refractory OC. (NCT01567891). CAR T cells specific for mesothelin, which is overexpressed in pancreatic and OC, are being used in a Phase I study of metastatic mesothelin-positive cancers (NCT02159716).

Oncolytic Viruses

Modified viruses that preferentially kill cancer cells or confer susceptibility to other drugs are another promising mode of immune therapy for OC. Myxoma virus infects human cancer cells while sparing normal tissue and is oncolytic in rodent models, reviewed elsewhere,131 and has demonstrated oncolytic activity against ascites-derived human OC cells ex vivo.132 However, there are no published OC trials utilizing myxoma virus. In vitro, reovirus is oncolytic against human OC cells.133 Neutralizing antibodies in malignant ascites can inactivate reovirus oncolytic activity, prompting approaches to overcome this limitation by loading reovirus onto immature DCs or lymphokine-activated killer cells.134 A Phase I trial of reovirus in platinum-resistant OC patients is ongoing (NCT00602277). A Phase I trial demonstrated the safety of an oncolytic measles virus that expresses the sodium/iodide symporter after intraperitoneal injection where a 26-month overall survival in this small cohort was observed, with no dose-limiting toxicities.135 An ongoing Phase I/II study is using intraperitoneal injected mesenchymal stem cells infected with oncolytic measles virus encoding thyroidal sodium/iodide symporter in patients with recurrent OC (NCT02068794). An ongoing study with oncolytic herpes simplex virus in patients with advanced OC uses a herpes virus vector to force tumor expression of thymidine kinase followed by treatment with valacyclovir (a thymidine kinase inhibitor) to kill transduced tumor cells (NCT01997190).

A summary of recent selected clinical trials using vaccines, adoptive cell transfers, and oncolytic viruses is presented in Table 13.2.

Table 13.2 Selected Clinical Trials in OC that Use Vaccines, Adoptive Cell Transfers, or Oncolytic Viruses

Clinical Trial Approach

Clinical Trial

No. OC Patients

Objective Responses

Reference or Trial ID

Vaccines

Phase II trial of recombinant vaccinia and fowlpox vaccines

expressing NY-ESO-1, 2012

22

21 mos PFS,

4 year OS

104

Phase II trial of subcutaneous or intravenous p53 peptide vaccination, 2012

13

4.2 mos PFS, 40.8 mos OS

106

Phase II trial of p53-synthetic long peptide vaccine, 2012

20

No increase in OS

107

Phase II trial of Trovax (5T4 antigen in vacinnia virus vector) for asymptomatic relapsed OC, ongoing

N/A

N/A

NCT01556841

Phase II FANG vaccine for stage III or IV OC patients, ongoing

N/A

N/A

NCT01551745

Phase I/II trial of CDX-1401 (DC-targeted NY-ESO-1) with TLR3 agonist and IDO-1 inhibitor for OC patients in remission, ongoing

N/A

N/A

NCT02166905

Phase Ib trial of E39/J65 (folate binding proteins) vaccine for OC patients in remission, ongoing

N/A

N/A

NCT02019524

Phase I trial of Her2 vaccine for solid tumors including OC, ongoing

N/A

N/A

NCT01376505

Adoptive Cell Transfers

Phase II trial of p53-pulsed dendritic cells vaccine, 2012

6

8.7 mos PFS, 29.6 mos OS

106

Phase I/II vaccination trial of Her2/neu, telomerase, and PADRE peptide-pulsed DCs ± cyclophosphamide, 2012

11

90% 3 year OS,

NED in 6 pts at 3 yrs

118

Phase I trial of autologous tumor lysate-pulsed dendritic cells + bevacizumab, cyclophosphamide, and autologous tumor lysate-primed T cells, 2013

6

2–PR, 2–SD, 2–PD

119

Pilot study of MUC1-primed cytotoxic T lymphocyte transfer, 2012

7

1–CR, 6–PD

125,126

Phase I trial of anti-mesothelin CAR T cells, ongoing

N/A

N/A

NCT02159716

Phase I trial of anti-mesothelin CAR T cells + chemotherapy, ongoing

N/A

N/A

NCT01583686

Phase I trial of anti-VEGFR2 CD8+ CAR T cells + chemotherapy, ongoing

N/A

N/A

NCT01218867

Oncolytic Viruses

Phase I trial of CA-125- or Na/I symporter-expressing measles virus, ongoing

N/A

N/A

NCT00408590

Phase I/II trial of Na/I symporter-expressing measles virus infected mesenchymal stem cells, ongoing

N/A

N/A

NCT02068794

Phase II trial of thymidine kinase-inactivated vaccinia virus, ongoing

N/A

N/A

NCT02017678

Phase I/II trial of oncolytic adenovirus, ongoing

N/A

N/A

NCT02028117

Phase II trial of oncolytic reovirus, ongoing

N/A

N/A

NCT02028117

Phase I trial of oncolytic reovirus, ongoing

N/A

N/A

NCT00602277

Phase I trial of thymidine kinase transducing herpesvirus vector plus valacyclovir

N/A

N/A

NCT01997190

NOTE: OC = ovarian cancer; PD = progressive disease; IR = initial response; CR = complete response; CCR = continued clinical response; PR = partial response; SD = stable disease; NED = no evidence of disease; NR = no response; N/A = not available; PFS = progression-free survival; OS = overall survival; pts = patients.

Conclusion

Advances in the identification of numerous cancer immunotherapeutic targets and in the translation of novel agents has produced great excitement in the potential of immunotherapy to become the next pillar of treatment in the oncologist’s arsenal. In the case of OC, there are currently no FDA-approved immunotherapies, but ongoing preclinical studies and clinical trials continue to generate promising leads. Within the next decade, it is reasonable to expect that important advances in OC immunotherapy will be made, leading to important Phase II and III trials and possible FDA approval of immunotherapy for OC. Promising leads from CAR T cell trials and combinations of immune checkpoint inhibitors could lead to important advances. With the recognition that tumor mutational burden is generally directly proportional to immunogenicity, and that OC has a low mutational burden relative to other carcinomas, strategies to boost OC immunogenicity (e.g., epigenetic modifiers, targeting viruses, interferons) could become important adjuncts and deserve additional study. Because OC also has relatively few conserved tumor antigens, strategies to personalize immunotherapy (e.g., whole tumor vaccines, peptides from individual tumor proteomic analyses) deserve more attention. In this regard, the concept that certain OC subtypes are more immunogenic (such as clear cell histologies) deserves additional attention. Checkpoint inhibitors successful in other carcinomas are showing only modest effects thus far in OC. Perhaps other checkpoint inhibitors will be more effective, or OC-specific adjuncts will be useful and needed. For example, we have shown how Treg depletion improves anti-PD-L1 effects in an OC preclinical model. Other OC-specific immune dysfunctional attributes deserve additional attention to determine if there are clinically exploitable leads, as we expect. For example, myeloid cells appear particularly dysfunctional in OC.8,136,137 We recently showed that tumor-intrinsic PD-L1 induces novel immunopathogenesis in OC138 and in collaboration with the Conejo-Garcia group that estrogens have off-tumor detrimental effects on OC myeloid cells,139 both concepts of which are clinically actionable. Because of a lack of curative salvage treatment options for chemorefractory OC, every clinician should counsel patients about referral to clinical trials, including OC immunotherapy trials, and patients should ask their treating physicians about clinical trial options.

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